EP0475619B1 - Catalyzed sucrose-6-ester process - Google Patents

Catalyzed sucrose-6-ester process Download PDF

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EP0475619B1
EP0475619B1 EP91307776A EP91307776A EP0475619B1 EP 0475619 B1 EP0475619 B1 EP 0475619B1 EP 91307776 A EP91307776 A EP 91307776A EP 91307776 A EP91307776 A EP 91307776A EP 0475619 B1 EP0475619 B1 EP 0475619B1
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sucrose
mmol
distannoxane
reaction
water
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EP0475619A1 (en
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Nicholas M. Vernon
Jr. Robert E. Wingard
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Johnson and Johnson Consumer Inc
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McNeil PPC Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings

Definitions

  • the invention relates to a process for the regioselective esterification of sucrose utilizing a distannoxane diester as a catalyst.
  • the esterification reaction is accelerated by a tertiary amine.
  • sucrose contains three primary hydroxyl groups and five secondary hydroxyl groups. Therefore, when it is desired to prepare derivatives of sucrose involving reaction of the hydroxyl groups, it can be a major synthesis problem to direct the reaction only to the desired hydroxyl groups.
  • the artificial sweetener 4,1′,6′-trichloro-4,1′,6′-trideoxy galacto sucrose ("sucralose”) is derived from sucrose by replacing the hydroxyls in the 4, 1′, and 6′ positions with chlorine. (In the process of making the sweetener, the stereo configuration at the 4 position is reversed - hence the compound is a galacto sucrose.) This compound and methods for synthesizing it are disclosed in U. S. Patent Nos.
  • a suitable di(hydrocarbyl)tin-based species such as dibutyltin oxide, dioctyltin oxide, dibutyltin dimethoxide, and the like
  • a hydroxyl-group containing compound such as a monohydric alcohol or a simple phenol
  • a reactive distannoxane intermediate i.e., a 1,3-di(hydrocarbyloxy)-1,1,3,3-tetra(hydrocarbyl)distannoxane
  • sucrose i.e., a 1,3-di(hydrocarbyloxy)-1,1,3,3-tetra(hydrocarbyl)distannoxane
  • the Navia process for the preparation of sucrose-6-esters (S-6-E) consists of three distinct steps, as is shown by the following set of equations which employ for the sake of exemplification dibutyltin oxide hemihydrate (DBTO ⁇ 1 ⁇ 2H2O) as the di(hydrocarbyl)tin oxide, n -butanol as the monohydric alcohol, acetic anhydride as the acylating agent, and N,N-dimethylformamide (DMF) as the acylation solvent.
  • DBTO ⁇ 1 ⁇ 2H2O dibutyltin oxide hemihydrate
  • n -butanol the monohydric alcohol
  • acetic anhydride as the acylating agent
  • DMF N,N-dimethylformamide
  • DBTO ⁇ 1 ⁇ 2H2O is refluxed with a stoichiometric excess of n -butanol in conjunction with the azeotropic removal of the water of condensation to generate 1,3-dibutoxy-1,1,3,3-tetrabutyldistannoxane monohydrate (DBDS ⁇ H2O).
  • sucrose-6-acetate (S-6-A) preparation DBDS ⁇ H2O is reacted with a roughly stoichiometric amount of sucrose (represented as SUCOH) in DMF with removal of water and n -butanol to produce 1,3-di-(6-O-sucrose)-1,1,3,3-tetrabutyldistannoxane, or dibutyldistannoxylsucrose (DBSS).
  • the third step of the process involves treating the hydroxylic solvent-free DBSS solution with a slight stoichiometric excess of acetic anhydride.
  • S-6-A is typically produced in good yields, with only minimal contamination by residual sucrose, sucrose diacetates, and other sucrose monoacetates.
  • DHTO di(hydrocarbyl)tin oxide
  • a polar aprotic solvent such as a tertiary amide
  • hydrocarbon-like cosolvent capable of both promoting the dissolution of the DHTO and affecting the codistillative removal of all water generated in the system, to produce an organotin-sucrose adduct.
  • adducts are distannoxanes of structures identical to those produced by the Navia method [i.e., they are 1,3-di-(6-O-sucrose)-1,1,3,3-tetra(hydrocarbyl)distannoxanes].
  • sucrose-substituted distannoxanes produced by the Neiditch et al. process can be readily acylated in situ to afford good yields of S-6-E.
  • This improved two-step process is depicted below for the case of DBTO ⁇ 1 ⁇ 2H2O, acetic anhydride, and DMF.
  • various di(hydrocarbyl)tin-based species such as dibutyltin oxide and 1,3-dibutoxy-1,1,3,3,-tetrabutyldistannoxane, are shown as possessing water of hydration. These waters of hydration were quantitated by several methods, the most useful of which were Karl Fischer water assays of the substances dissolved in glacial acetic acid. These waters of hydration are released in various of the reactions whose equations are pictured herein, and in all such cases the stoichiometry shown in the equations has been demonstrated in the laboratory. * see European Patent Application EP-A-454,386
  • anhydrous acylation product mixture of each process comprised primarily of S-6-E, DSDE, and polar aprotic solvent, can be treated with a relatively small amount of water (molar basis) and the DSDE then almost exclusively extracted as a monohydrate with extraordinary efficiency by an appropriate hydrocarbon-like immiscible solvent.
  • Vernon et al. disclose that the anhydrous acylation product mixture of each process, comprised primarily of S-6-E, DSDE, and polar aprotic solvent, can be treated with a relatively small amount of water (molar basis) and the DSDE then almost exclusively extracted as a monohydrate with extraordinary efficiency by an appropriate hydrocarbon-like immiscible solvent.
  • the recovered DSDE ⁇ H2o could be recycled by either: (a) reaction with an alkali metal salt of a hydrocarbonol to regenerate a 1,3-di(hydrocarbyloxy)-1,1,3,3-tetra(hydrocarbyl)distannoxane for reuse in the process of Navia; or (b) reaction with an alkali metal hydroxide to regenerate a di(hydrocarbyl)tin oxide for reuse in the process of Neiditch et al.
  • sucrose may be treated with a DSDE ⁇ H2O in a polar aprotic vehicle to (presumably) produce a sucrose-distannoxane diester coordination complex which can be regioselectively acylated in situ , either with or without a tertiary amine accelerator, to produce S-6-E.
  • a sucrose-distannoxane diester coordination complex which can be regioselectively acylated in situ , either with or without a tertiary amine accelerator, to produce S-6-E.
  • the DSDE ⁇ H2O may be recovered from acylation media according to the principles set out in Vernon et al., and that it may then be directly reused for S-6-E production following the teachings of this invention.
  • the DSDE ⁇ H2O component of this process can be employed in stoichiometric proportions that are substantially less than the corresponding equivalent amount of sucrose undergoing acylation.
  • the benzoylation of sucrose may be catalyzed by DSDA ⁇ H2O without the formation of a detectable amount of sucrose-6-acetate or related acetate esters, thereby inferring the absence of free acetate ions in the reaction mixture.
  • the process is catalytic with respect to the DSDE ⁇ H2O (or DSDE) component, and we believe that the reactive intermediate (towards acylation) is a coordinate covalently bonded adduct (i.e., a donor-acceptor or coordination complex) formed between sucrose and a metal atom of the distannoxane diester catalyst.
  • a coordination complex is defined as a compound containing one or more coordinate covalent bonds, and a coordinate covalent bond is defined as a bond between two atoms in which one of the two atoms supplies both electrons.
  • Tetravalent organotin compounds have a well known propensity for forming penta- and hexacoordinate species if groups with ligand properties, such as hydroxyls, are present.
  • groups with ligand properties such as hydroxyls
  • organotin-mannose derivative containing both five- and six-coordinate tin atoms in the solid state consult C. Holzapfel, et al., S. Afr. J. chem. , 35 , 81 (1982).]
  • the process of the invention comprises reacting sucrose with an acylating agent in a polar aprotic reaction vehicle and in the presence of a catalytic quantity of a 1,3-diacyloxy-1,1,3,3-tetra(hydrocarbyl)distannoxane, or distannoxane diester, for a period of time and at a temperature sufficient to produce a sucrose-6-ester.
  • the reaction is carried out in the presence of a tertiary amine accelerator.
  • sucrose-6-esters The organotin-mediated regioselective 6-position acylations of sucrose to produce sucrose-6-esters are described in the Navia and the Neiditch et al. patent applications described above.
  • the utility of sucrose-6-esters in a process for producing the artificial sweetener 4,1′,6′-trichloro-4,1′,6′-trideoxy galacto sucrose is described, for example, in the Navia and the Neiditch et al. patent applications described above, as well as in Walkup et al., IMPROVED SUCROSE-6-ESTER CHLORINATION, United States Application Serial No. 382,147* , filed July 18, 1989, and assigned to the same assignee as this application. * See EP-A-0409549
  • Equation (1) shows how the process is believed to proceed when DSDA ⁇ H2O is employed as catalyst
  • Equation (2) shows how the process is believed to proceed when anhydrous DSDA is used.
  • DSDA ⁇ X is intended to represent a coordinate covalently bonded adduct or coordination complex formed between DSDA and "X".
  • the anhydrous amine-accelerated process is detailed in the following set of four sequential equations which for the sake of exemplification employ DSDA ⁇ H2O as the 1,3-diacyloxy-1,1,3,3-tetra(hydrocarbyl)distannoxane monohydrate, triethylamine as the tertiary amine, acetic anhydride as the acylating agent, and DMF as the acylation solvent.
  • Equation (3) shows the reaction of DSDA ⁇ H2O with sucrose to produce a reactive (towards acylation) distannoxane-sucrose coordination complex.
  • Equation (4) shows the reaction of acetic anhydride with triethylamine to produce a highly reactive activated complex (i.e., an acyl trialkylammonium salt), which functions as the actual acylating agent in this process.
  • Equation (5) depicts the reaction of the sucrose coordination complex (produced in equation 3) with the acyl ammonium complex (produced in equation 4) to generate sucrose-6-acetate and spent (i.e., no longer complexed to sucrose) distannoxane diacetate.
  • Equation (6) shows the reaction of free (and as yet unreacted) sucrose with spent DSDA to generate fresh distannoxane-sucrose coordination complex.
  • Equations (3) through (6) show the generation and utilization of the highly reactive activated ammonium acylating complex. It is the presence of this species which provides extraordinarily rapid acylation rates, and which render the amine-accelerated acylation reaction suitable for practice in a continuous processing mode.
  • the invention may be practiced in any of several different, but closely related, manners.
  • the first method simply involves dissolving sucrose and the requisite amount of DSDE ⁇ H2O catalyst in a polar aprotic solvent (mild heating usually required), and then treating the solution thus produced with a carboxylic acid anhydride at or slightly above room temperature. After the acylation is complete, the solution is treated with a small amount of water and the DSDE ⁇ H2O recovered for reuse by extraction.
  • the acylation product mixture which at this point consists primarily of S-6-E and lesser amounts of other sucrose monoesters, sucrose diesters, and residual sucrose in a medium consisting of polar aprotic solvent, carboxylic acid, and water, can then be freed of carboxylic acid and dried (e.g., by vacuum distillation) and subjected to chlorination to produce a sucralose-6-ester (TGS-6-E) according to the teachings of the Walkup et al. patent application, cited above.
  • TGS-6-E sucralose-6-ester
  • Example 5 This mode of practice of the invention is illustrated by Examples 1-12.
  • Example 5 1.00 molar equivalent of sucrose and 0.50 molar equivalent of DSDA ⁇ H2O were dissolved in DMF at 75°C, and the solution thus produced cooled to ambient temperature and treated with 1.10 molar equivalents of acetic anhydride. After stirring for about 18 hr at ambient temperature, the reaction solution was treated with water and extracted with cyclohexane (to recover DSDA ⁇ H2O). Partial evaporation of the DMF solution gave a syrup shown by HPLC analysis to contain a 65% yield of S-6-A.
  • Polar aprotic solvents which have been employed in the laboratory are DMF and N-methyl-2-pyrrolidione (NMP).
  • suitable solvents include dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and hexamethylphosphoramide (HMPA).
  • DMSO dimethyl sulfoxide
  • DMA N,N-dimethylacetamide
  • HMPA hexamethylphosphoramide
  • Stoichiometric ratios of carboxylic acid anhydride ranging from about 1.00 to about 4.00 molar equivalents (basis sucrose) have demonstrated experimental utility.
  • Preferred stoichiometric ratios are in the range of from about 1.10 to about 1.80 molar equivalents.
  • Stoichiometric ratios below about 1.10 molar equivalents can lead to an undesirable amount of unreacted sucrose in the final product, while ratios above about 1.80 can cause the formation of undesirable sucrose mono- and diesters.
  • Acylation reaction temperatures ranging from about 0°C to about 60°C have demonstrated experimental utility. This is not considered to be a particularly critical aspect of the invention, although acylation reaction temperature affects the rate of acylation and excessively high temperatures can increase the production of undesirable sucrose esters. Preferred acylation temperatures range from about 20°C to about 45°C.
  • acetic anhydride and benzoic anhydride have been shown to be effective acylating agents.
  • Acetic anhydride appears to be slightly superior. This is believed to be a result of either steric factors or inherent reactivity, or perhaps some combination of both.
  • a variety of other carboxylic acid anhydrides would be expected to function effectively in the practice of the invention.
  • DSDE ⁇ H2O-catalyzed acylations are generally substantially slower than those involving a 1,3-di-(6-O-sucrose)-substituted distannoxane. This is presumably a result of both the presence of a coordinate covalent bond between the 6-oxygen of sucrose and a tin atom (rather than a normal covalent bond), and the competition between sucrose and other species, such as water, solvent, and the carboxylic acid, for the coordination sites around the tin atom.
  • DSDE ⁇ H2O-catalyzed acylations can require from about 2 hr to about 48 hr to reach completion.
  • the rate of acylation is dependent upon a number of variables, which include catalyst stoichiometry (increasing catalyst concentration relative to sucrose increases the rate of acylation), activity of the catalyst (e.g., DSDA ⁇ H2O appears to be a more active catalyst than DSDB ⁇ H2O), reactivity of the carboxylic acid anhydride (e.g., acetic anhydride is more reactive than benzoic anhydride), and the reaction temperature and the relative concentration of the reactive species (as the acylation is a multi-order process).
  • catalyst stoichiometry increasing catalyst concentration relative to sucrose increases the rate of acylation
  • activity of the catalyst e.g., DSDA ⁇ H2O appears to be a more active catalyst than DSDB ⁇ H2O
  • reactivity of the carboxylic acid anhydride e.g., acetic anhydride is more reactive than benzoic anhydride
  • reaction temperature and the relative concentration of the reactive species as the acylation is
  • DSDE ⁇ H2O may be recovered for reuse according to the teachings of Vernon et al., cited above.
  • the acylation mixture is treated with a small amount of water and the DSDE ⁇ H2O extracted in an essentially quantitative manner by contacting the mixture with a hydrocarbon such as toluene, cyclohexane, n -heptane, 2,2,4-trimethylpentane, or mixtures thereof, or an ether such as diethyl ether, di( n -propyl) ether, methyl tert -butyl ether, or the like.
  • a hydrocarbon such as toluene, cyclohexane, n -heptane, 2,2,4-trimethylpentane, or mixtures thereof
  • an ether such as diethyl ether, di( n -propyl) ether, methyl tert -butyl ether, or the like.
  • the volatile extraction solvent is removed by, for example, vacuum evaporation to provide the recovered DSDE ⁇ H2O as a (typically) viscous oil which may then be redissolved in the polar aprotic solvent along with sucrose and the acylation process repeated.
  • the second mode for the practice of the invention involves the use of a DSDE ⁇ H2O catalyst in a dehydrated or partially dehydrated reaction system, as is illustrated by Examples 13-18.
  • the practice of this aspect of the invention begins by forming a slurry of sucrose and a distannoxane diester monohydrate in a mixed solvent system consisting of a polar aprotic solvent (as above) and a hydrocarbon-like cosolvent capable of removing all or part of the water of hydration of the distannoxane diester (plus any water present from the use of wet reactants or solvents) by codistillation.
  • the normally biphasic (but solids-free) reaction mixture is treated with a carboxylic acid anhydride at or slightly above room temperature.
  • the mixture is treated with a small amount of water and the DSDE recovered by extraction for reuse.
  • the acylation product mixture may then be further processed (i.e., the water, carboxylic acid, and residual extraction solvent removed) and subjected to chlorination to make TGS-6-E.
  • Example 16 for instance, 1.00 molar equivalent of sucrose and 1.05 molar equivalents of DSDA ⁇ H2O were slurried in an 8:3 (by volume) mixture of DMF and cyclohexane, and the mixture vigorously refluxed for 60 min in a reaction vessel equipped with a refluxive water separator. This removed 62% of the original DSDA ⁇ H2O water of hydration. The solids-free reaction mixture was then cooled to ambient temperature and treated with 1.10 molar equivalents of acetic anhydride and stirred for about 18 hr. Following this, the reaction mixture was treated with water, extracted with cyclohexane (to recover DSDA ⁇ H2O), and partially evaporated to give a DMF-based syrup shown by HPLC analysis to contain an 82% yield of S-6-A.
  • Cosolvents capable of codistillatively removing the water of hydration include saturated hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, ketones, and ethers.
  • a very wide range of solvents appear to be suitable for use as cosolvents in the invention.
  • the primary criteria for a cosolvent are that it produce a mixture with the polar aprotic solvent, the DSDE ⁇ H2O, and the sucrose which refluxes with an internal reaction temperature within the range of from about 75°C to about 125°C, that it codistill the water of hydration of the DSDE ⁇ H2O, and that it not render key reaction components (e.g., sucrose) insoluble.
  • Cosolvents which are immiscible with water and which do form a constant-composition minimum-boiling azeotrope with water are preferred, but the cosolvent does not have to be capable of forming a constant-boiling azeotrope of constant composition with water to be an effective cosolvent for the practice of the current invention. Nor is it necessary that the cosolvent be immiscible with water. It is necessary only that the cosolvent be capable of codistilling the water of hydration from the reaction medium.
  • Preferred cosolvents for reasons of chemical stability, efficiency of water removal, cost, and boiling point include cyclohexane, n -heptane, and isooctane (2,2,4-trimethylpentane).
  • the preferred dehydration temperature is between the range of about 85°C to about 105°C. Temperatures below about 85°C can result in an unnecessarily slow dehydration, while temperature greater than about 105°C can result in decomposition.
  • Reaction temperatures are typically controlled in an empirical manner by adjusting the ratio of the polar aprotic solvent to the lower boiling cosolvent.
  • Solvent to cosolvent ratios (by volume) of from about one-to-one to about ten-to-one are believed useful for the practice of this invention, with ratios of from about eight-to-five to about eight-to-one being preferred.
  • Solvent to cosolvent ratios are limited by practical considerations. Too much cosolvent will inhibit sucrose solubility and could produce a mixture with a boiling point too low for reasonable dehydration time. Too little cosolvent can limit the rate at which water can be codistilled from the reaction mixture, and can also result in dehydration temperatures high enough to cause thermal degradation of the carbohydrate species.
  • a wide range of solids (DSDE ⁇ H2O and sucrose) to solvents (polar aprotic solvent and sucrose) ratios are useful for the practice of the invention. This is not considered to be a particularly critical aspect of the invention, provided that there is sufficient polar aprotic solvent present to insure the partial dissolution of the sucrose, and sufficient cosolvent present to insure water removal and to provide a desirable reaction temperature.
  • solids-to-solvents ratios wt/vol
  • the more concentrated systems are preferred for reasons of economics and practicality.
  • the reflux time required for the full or partial dehydration of mixtures of DSDE ⁇ H2O and sucrose is strictly a function of the efficiency of the removal of water from the system by codistillation.
  • the efficiency of water removal from the reaction system is a function of a number of interactive variables. These variables, which to a large extent can be experimentally controlled, include: (a) the internal reaction temperature; (b) the boiling point of the cosolvent; (c) the water content of the codistillate; (d) the rate of heat input to the system; (e) the efficiency of agitation; and (f) the reactor configuration employed.
  • the third method of practice involves utilizing the basic chemistries of Navia and Neiditch et al. in conjunction with a stoichiometric insufficiency (relative to sucrose) of the relevant reactive organotin intermediate, which is 1,3-di(hydrocarbyloxy)-1,1,3,3-tetra(hydrocarbyl)distannoxane for the process of Navia and a di(hydrocarbyl)tin oxide for the process of Neiditch et al.
  • a stoichiometric insufficiency relative to sucrose
  • 1,3-di(hydrocarbyloxy)-1,1,3,3-tetra(hydrocarbyl)distannoxane for the process of Navia
  • a di(hydrocarbyl)tin oxide for the process of Neiditch et al.
  • the reactive (towards acylation) 1,3-di-(6-O-sucrose)-1,1,3,3-tetra(hydrocarbyl)distannoxane intermediates are generated in a substantially anhydrous polar aprotic environment in the presence of free (i.e., not covalently bound to tin) sucrose.
  • Reaction with a slight stoichiometric excess (basis sucrose) of acylating agent results in first the consumption of the covalently bound organotin-sucrose adduct to produce S-6-E and DSDE, followed by the DSDE-catalyzed acylation of the free sucrose present.
  • the stoichiometric insufficiency of reactive DHTO can be produced by removing (by codistillation) less than the required one mole of water (basis DHTO) from what would otherwise be a stoichiometrically sufficient quantity of DHTO.
  • Example 22 This mode of practice of the invention is illustrated by Examples 19-24.
  • Example 22 1.0 molar equivalent of sucrose was treated with 0.50 molar equivalent of dioctyltin oxide (DOTO.1 ⁇ 2H2O) in a refluxing heptane-DMF mixture for 4 hr.
  • DOTO.1 ⁇ 2H2O dioctyltin oxide
  • the anhydrous reaction mixture which at that point contained 0.50 molar equivalent of free sucrose and 0.25 molar equivalent of 1,3-di-(6-O-sucrose)-1,1,3,3-tetraoctyldistannoxane, was then cooled to about 5°C and treated with 1.10 molar equivalents of acetic anhydride to afford, after extraction of 1,3-diacetoxy-1,1,3,3-tetraoctyldistannoxane monohydrate (ODSDA ⁇ H2O), an 81% yield of S-6-A.
  • ODSDA ⁇ H2O 1,3-diacetoxy-1,1,3,3-tetraoctyldistannoxane monohydrate
  • Example 1 The experiment of Example 1 was repeated using 49.8 g (220 mmol) of benzoic anhydride for acylation.
  • the formation of sucrose-6-benzoate (S-6-B, R f 0.5) was monitored using the same TLC system. After stirring for three days, the reaction was worked-up to give a viscous oil determined by HPLC analysis to contain 40.6 g (90.9 mmol, 45.4% yield) of sucrose-6-benzoate.
  • Example 2 The experiment of Example 2 was repeated using 37.1 g (50.0 mmol) of DSDB ⁇ H2O as catalyst. After stirring at room temperature under argon for three days, the reaction was worked-up to produce a syrup determined by HPLC analysis to contain 36.8 g (82.5 mmol, 41.3% yield) of sucrose-6-benzoate.
  • Example 1 The experiment of Example 1 was repeated with 34.2 g (100 mmol) of sucrose, 18.6 g (25.0 mmol) of DSDB ⁇ H2O, 250 ml of DMF, and 11.2 g (110 mmol) of acetic anhydride to give a viscous oil determined by HPLC analysis to contain 21.0 g (54.6 mmol, 54.6% yield) of sucrose-6-acetate.
  • Example 1 The experiment of Example 1 was repeated using 61.2 g (100 mmol) of DSDA ⁇ H2O. After stirring for 20 hr at room temperature under argon, the reaction was worked-up to give a syrup determined by HPLC analysis to contain 49.8 g (130 mmol, 64.8% yield) of sucrose-6-acetate.
  • Example 5 The experiment of Example 5 was repeated using 49.8 g (220 mmol) of benzoic anhydride for acylation. After stirring for two days at room temperature under argon, the reaction was worked-up to produce a viscous oil determined by HPLC analysis to contain 56.3 g (126 mmol, 63.0%) of sucrose-6-benzoate.
  • Example 1 The experiment of Example 1 was repeated using 91.8 g (150 mmol) of DSDA ⁇ H2O. After stirring overnight at room temperature under argon, the reaction was worked-up to give a syrup determined by HPLC analysis to contain 53.6 g (140 mmol, 69.8% yield) of sucrose-6-acetate.
  • Example 7 The experiment of Example 7 was repeated using 49.8 g (220 mmol) of benzoic anhydride for acylation. After stirring for two days at room temperature under argon, the reaction was worked-up to give a viscous oil determined by HPLC analysis to contain 58.9 g (132 mmol, 66.0% yield) of sucrose-6-benzoate.
  • Example 9 The experiment of Example 9 was repeated using 49.8 g (220 mmol) of benzoic anhydride for acylation. After stirring for two days at room temperature under argon, the solution was worked-up to produce a syrup shown by HPLC analysis to possess 53.0 g (119 mmol, 59.4% yield) of sucrose-6-benzoate.
  • Tetraoctyldistannoxane diacetate monohydrate was prepared by dissolving 37.9 g (100 mmol) of DOTO ⁇ 1 ⁇ 2H2O in 400 ml of glacial acetic acid at 80°C (about 15 min required). Rotary evaporation (water-aspirator vacuum, 65°C water bath) afforded the product as a pale-yellow viscous oil. The oil was dissolved in 500 ml of DMF, and the solution partially evaporated (rotary evaporator, mechanical-pump vacuum, 30°C water bath) to remove the residual acetic acid (final volume about 300 ml). The yield was assumed to be quantitative (43.0 g, 50.0 mmol).
  • Example 1 The experiment of Example 1 was repeated using the above-described DMF solution of the tetraoctyl derivative, 34.2 g (100 mmol) of sucrose, and 11.2 g (110 mmol) of acetic anhydride. After stirring overnight at room temperature under argon, the reaction mixture was worked-up to give a syrup shown by HPLC assay to contain 25.4 g (66.1 mmol, 66.1% yield) of sucrose-6-acetate.
  • DSDA ⁇ H2O was prepared by dissolving 51.6 g (200 mmol) of DBTO ⁇ 1 ⁇ 2H2O in 400 ml of glacial acetic acid at room temperature (about 5 min required).
  • Rotary evaporation water-aspirator vacuum, 50°C water bath
  • the oil was dissolved in 750 ml of NMP, and the solution partially evaporated (rotary evaporator, mechanical-pump vacuum, 50°C water bath) to remove the residual acetic acid (final volume about 500 ml).
  • the yield was assumed to be quantitative (61.2 g, 100 mmol).
  • Example 5 The experiment of Example 5 was repeated using the above-described NMP solution. After stirring at room temperature overnight, the reaction mixture was worked-up to afford a syrup shown by HPLC analysis to possess 40.1 g (104 mmol, 52.2% yield) of sucrose-6-acetate.
  • the slurry was cooled to about 5°C, treated dropwise over about 10 min with 22.5 g (220 mmol) of acetic anhydride, and stirred for an additional 60 min at about 5°C.
  • the anhydride addition produced a mild (less than 5°C) exotherm.
  • the reaction mixture was treated with water (50 ml), extracted with cyclohexane (2 x 500 ml) to remove DSDA ⁇ H2O, and the DMF evaporated (rotary evaporator, mechanical-pump vacuum, 30°C water bath) to afford a dark-brown viscous oil determined by HPLC analysis to contain 39.0 g (102 mmol, 50.8% yield) of sucrose-6-acetate.
  • Example 13 The experiment of Example 13 was repeated using 61.2 g (100 mmol) of DSDA ⁇ H2O for catalysis.
  • the dehydration temperature was 92°C (2-hr reflux).
  • Work-up provided a syrup containing 50.9 g (132 mmol, 66.3% yield) of sucrose-6-acetate.
  • Example 13 The experiment of Example 13 was repeated using 91.8 g (150 mmol) of DSDA ⁇ H2O as catalyst.
  • the dehydration temperature was 92°C (1.5-hr reflux). Work-up afforded a syrup containing 51.9 g (135 mmol, 67.6% yield) of sucrose-6-acetate.
  • the solids-free mixture was cooled to about 20°C, and treated dropwise over about 3 min with 22.5 g (220 mmol) of acetic anhydride. During the anhydride addition, ice-bath cooling was used as needed to keep the reaction temperature below 25°C. After stirring overnight at room temperature, the reaction mixture was worked-up as described in Example 13 to provide a syrup shown by HPLC analysis to contain 62.9 g (164 mmol, 82.0% yield) of sucrose-6-acetate.
  • Example 16 The experiment of Example 16 was repeated using 49.8 g (210 mmol) of benzoic anhydride for acylation.
  • the dehydration temperature was 95°C (60-min reflux). Work-up afforded a syrup containing 65.9 g (148 mmol, 73.8% yield) of sucrose-6-benzoate.
  • Example 16 The experiment of Example 16 was repeated using 34.2 g (100 mmol) of sucrose, 91.8 g (150 mmol) of DSDA ⁇ H2O, 400 ml of DMF, 150 ml of isooctane, and 11.2 g (110 mmol) of acetic anhydride.
  • the reaction temperature was 107°C (45-min reflux). Work-up afforded a syrup containing 31.2 g (81.1 mmol, 81.1% yield) of sucrose-6-acetate.
  • the slurry was cooled to about 5°C, treated dropwise over 10 min with 49.8 g (220 mmol) of benzoic anhydride dissolved in 50 ml of ice-cold DMF, and stirred for an additional 60 min at about 5°C. After stirring overnight at room temperature under argon, the reaction mixture was filtered to remove undissolved sucrose, treated with water (50 ml), extracted with cyclohexane (2 x 500 ml) to remove DSDB ⁇ H2O, and the DMF evaporated (rotary evaporator, mechanical-pump vacuum, 30°C water bath) to afford a syrup determined by HPLC analysis to contain 39.2 g (87.8 mmol, 43.9% yield) of sucrose-6-benzoate.
  • Example 19 The experiment of Example 19 was repeated using 25.8 g (100 mmol) of DBTO ⁇ 1 ⁇ 2H2O.
  • the reaction temperature was 99°C (6-hr reflux).
  • this reaction mixture was solids-free throughout the reflux and benzoylation periods. Work-up afforded a syrup containing 75.5 g (169 mmol, 84.7% yield) of sucrose-6-benzoate.
  • Example 19 The experiment of Example 19 was repeated using 68.5 g (200 mmol) of sucrose, 25.8 g (100 mmol) of DBTO ⁇ 1 ⁇ 2H2O, 400 ml of DMF, 100 ml of cyclohexane, and 22.5 g (220 mmol) of acetic anhydride.
  • the dehydration temperature was 99°C.
  • the reaction was solids-free throughout the reflux and acetylation. Work-up afforded a syrup shown by HPLC analysis to contain 61.0 g (159 mmol, 79.4% yield) of sucrose-6-acetate.
  • Example 19 The experiment of Example 19 was repeated using 37.9 g (100 mmol) of DOTO ⁇ 1 ⁇ 2H2O and 22.5 g (220 mmol) of acetic anhydride. The dehydration temperature was 99°C (4-hr reflux). This reaction remained solids-free throughout the reflux and acetylation. Work-up afforded a syrup shown by HPLC analysis to contain 62.0 g (161 mmol, 80.7% yield) of sucrose-6-acetate.
  • Example 23 The experiment of Example 23 was repeated with 12.9 g (50.0 mmol) of DBTO ⁇ 1 ⁇ 2H2O. After stirring for 9 days, work-up provided a syrup which contained 16.3 g (36.5 mmol, 73.0% yield) of sucrose-6-benzoate.
  • Example 16 The cyclohexane extracts produced in Example 16 were combined, washed with 200 ml of 50% saturated aqueous brine, and subjected to rotary evaporation (water-aspirator vacuum, 30°C water bath followed by mechanical-pump vacuum, 40°C water bath) to produce 122.6 g (200 mmol) of recovered DSDA ⁇ H2O.
  • This viscous tan oil was treated with 150 ml of cyclohexane, and the resulting solution employed in a repeat of Example 16.
  • the reaction temperature was 93°C (60-min reflux). Work-up afforded a syrup containing 60.5 g (158 mmol, 78.8% yield) of sucrose-6-acetate.
  • DBTO ⁇ 1 ⁇ 2H2O (103 g, 0.40 mol) iss refluxed with acetic or benzoic acid (24.1 g or 49.1 g, 0.40 mol) in toluene or cyclohexane (200-400 ml) for about 2 hr with the water of reaction being separated in a Dean-Stark trap.
  • the DSDE ⁇ H2O could be used in solution, or crystallized by solvent removal and dissolution in either 200 ml of 5% aqueous acetonitrile (DSDB ⁇ H2O) or 100 ml of 5% aqueous DMF (DSDA ⁇ H2O).
  • DSDA ⁇ H2O displays a melting point of 57-8°C a , and provids a satisfactory elemental analysis (calcd for C20H42O5Sn2 ⁇ H2O:C, 39.39; H, 6.83. found: C, 38.87; H, 6.83).
  • DSDB ⁇ H2O displays a melting point of 94-6°C, and also provids a satisfactory elemental analysis (calcd for C30H46O5Sn2 ⁇ H2O:C, 48.55; H, 6.52. found: C, 47.26; H, 6.24). a lit mp 58-60°C [D. Alletson, et al., J. Chem. Soc. , 5469, (1963)].
  • the invention may be carried out in a variety of different modes. These modes are differentiated, in part, by: (a) the extent of dehydration of the DSDE ⁇ H2O employed as organotin agent; (b) the nucleophilicity of the tertiary amine employed; (c) the method of recovery employed for the S-6-E product; (d) the method of recovery and recycle employed for the tertiary amine component; and (e) the method of recovery and recycle used for the DSDE ⁇ H2O component. Those methods of practice which involve continuous processing are preferred.
  • the first two of these modes involve batchwise processing, while the latter three involve continuous processing.
  • the first mode simply involves dissolving sucrose and the requisite amount of DSDE ⁇ H2O catalyst in a polar aprotic solvent (mild heating usually required) and then sequentially treating the solution thus produced with a low-boiling (relative to the polar aprotic solvent) tertiary amine and a carboxylic acid anhydride at or slightly below room temperature.
  • the acylation product mixture which at this point consists primarily of S-6-E (and lesser amounts of other sucrose esters and residual sucrose) in a medium consisting of polar aprotic solvent, water, tertiary amine, and carboxylic acid, can then be freed of low-boiling tertiary amine (e.g., by vacuum evaporation or treatment with a cation exchange resin), carboxylic acid (e.g., by vacuum evaporation or treatment with an anion exchange resin), and water (e.g., by vacuum evaporation or treatment with a dehydrating agent) to produce a syrup from which the S-6-E may be isolated by crystallization or precipitation techniques.
  • purified and dried DMF-based syrups may be subjected to chlorination to produce a sucralose-6-ester according to the teachings of Walk
  • Example 27 This mode of practice of the invention is illustrated by Examples 27 and 28 herein.
  • Example 27 by way of illustration, 1.00 molar equivalent of sucrose and 0.50 molar equivalent of DSDA ⁇ H2O were dissolved in DMF at 75°C, and the solution thus produced cooled to room temperature and treated sequentially with toluene, triethylamine (1.10 molar equivalents), and acetic anhydride (1.10 molar equivalents). After stirring for 30 min at ambient temperature, the reaction solution was treated with water and extracted with cyclohexane (to recover DSDA ⁇ H2O). Vacuum evaporation was employed to remove triethylamine, acetic acid, water, and a portion of the DMF to give a syrup found to contain a 64% yield of S-6-A.
  • DSDE ⁇ H2O concentration in the reaction mixture is high, it is advantageous to add a small amount (5-20 vol %) of a hydrocarbon-like cosolvent to keep it in solution.
  • a hydrocarbon-like cosolvent has demonstrated utility for this purpose.
  • Other useful cosolvents include benzene, mixed xylenes, cyclohexane, methyl tert -butyl ether, chloroform, and the like.
  • Stoichiometric ratios of low-boiling tertiary amine ranging from about 1.00 to about 1.25 molar equivalents (basis sucrose) have been employed.
  • Preferred stoichiometric ratios are in the range of from about 1.05 to about 1.10 molar equivalents, and are equal to the molar equivalents of carboxylic acid anhydride being employed in that specific process.
  • the use of less tertiary amine than acid anhydride (molar basis) will cause a significant decrease in the rate of acylation.
  • the use of a stoichiometric excess of tertiary amine can result in lowered yields if side reaction with the organotin catalyst, initiated by the tertiary amine, occur.
  • a large assortment of low-boiling tertiary amines are suitable for use in this mode of practice of the invention.
  • Key criteria for this process component are that it not produce an excessive amount of side reaction with the DSDE ⁇ H2O catalyst (some tertiary amines, such as for example imidazole and 1,8-diazabicyclo[5.4.0]undec-7-ene, fairly rapidly impair the utility of these catalysts), that it possess sufficient nucleophilicity to react with the carboxylic acid anhydride to produce an acyl ammonium activated complex, and that it be easily removed (by, for example, vacuum evaporation) to provide for the ready isolation of the S-6-E as either a solid or purified syrup.
  • Tertiary amines which have been employed successfully include trialkylamines such as trimethylamine (TMA), triethylamine (TEA), and diisopropylethylamine (DEA), and aromatic heterocyclic amines such as pyridine and 2,6-lutidine (2,6-dimethylpyridine).
  • TMA trimethylamine
  • TEA triethylamine
  • DEA diisopropylethylamine
  • aromatic heterocyclic amines such as pyridine and 2,6-lutidine (2,6-dimethylpyridine).
  • Other appropriate amines would include diethylmethylamine, dimethylethylamine, and the picolines (methylpyridines).
  • Preferred tertiary amines include TMA and TEA because of cost and ease of removal by vacuum evaporation.
  • amine-accelerated acylations are generally substantially faster than those involving 1,3-di-(6-O-sucrose)-substituted distannoxanes. This is presumably a result of the great reactivity of the acyl ammonium salt, which is the de facto acylating agent. Amine-accelerated acylations can require from about 3 min to about 60 min to reach completion.
  • the rate of regioselective acylation is dependent upon a number of variables, which include catalyst stoichiometry (increasing catalyst concentration relative to sucrose increases the rate), activity of the catalyst (e.g., DSDA ⁇ H2O appears to be a more active catalyst than DSDB ⁇ H2O), nucleophilicity of the tertiary amine employed (e.g., triethylamine is more nucleophilic than pyridine and hence produces a higher concentration of the acyl ammonium salt thereby affording a faster reaction rate), reactivity of the carboxylic acid anhydride (e.g., acetic anhydride is more reactive than benzoic anhydride), and the reaction temperature and the relative concentration of the reactive species (as the acylation is a multi-order process).
  • catalyst stoichiometry increasing catalyst concentration relative to sucrose increases the rate
  • activity of the catalyst e.g., DSDA ⁇ H2O appears to be a more active catalyst
  • DSDE ⁇ H2O may be recovered for reuse according to the teachings of Vernon et al., as discussed above.
  • the low-boiling tertiary amine may be recovered by fractional distillation techniques following the extraction of the DSDE ⁇ H2O.
  • a DSDE-free DMF-based S-6-E solution can be "stripped" (using, for example, a thin-film evaporator) of low-boiling tertiary amine (such as trimethylamine, bp 3°C), water (bp 100°C), and a portion of the DMF (bp 153°C) to produce a distillate from which the tertiary amine can be readily recovered by fractional distillation.
  • the DSDE-free DMF-based S-6-E solution can be carefully fractionally distilled to recover the tertiary amine.
  • the acid can be removed by the use of an appropriate anion exchange resin following the DSDE ⁇ H2O extraction.
  • the.water can be removed by the use of a dehydrating agent (such as molecular sieves) following the DSDE ⁇ H2O extraction.
  • the second mode for the practice of the amine-accelerated aspect of the invention involves the use of a DSDE ⁇ H2O catalyst in a dehydrated or partially dehydrated reaction system as is illustrated by Examples 29 through 45 herein.
  • This mode of practice is conducted in a manner similar to that described above for that mode of practice of the invention conducted under dehydrated or partially dehydrated reaction conditions, but containing no amine accelerator.
  • the solution is treated with a small amount of water and the DSDE ⁇ H2O recovered by extraction for reuse.
  • the acylation product mixture may then be further processed (i.e., the water, tertiary amine, carboxylic acid, and residual extraction solvent removed) and the S-6-E isolated as a solid (e.g., by crystallization or precipitation) or, for the case of DMF-based syrups, subjected to chlorination to make a sucralose-6-ester.
  • Example 36 for illustration, 1.00 molar equivalent of sucrose and 1.00 molar equivalent of DSDB ⁇ H2O were slurried in a 4:1 (by volume) mixture of DMF and cyclohexane, and the mixture vigorously refluxed for 30 min in a reaction vessel equipped with a refluxive water separator. This removed 40% of the original DSDB ⁇ H2O water of hydration. The solids-free reaction mixture was then cooled to ambient temperature and treated sequentially with 1.10 molar equivalents of triethylamine and 1.10 molar equivalents of acetic anhydride.
  • reaction mixture was treated with water, extracted with cyclohexane (to recovery DSDB ⁇ H2O), and partially evaporated (to remove triethylamine, water, acetic acid, and a portion of the DMF) to produce a syrup shown by HPLC analysis to contain an 84% yield of sucrose-6-acetate.
  • the normally biphasic (but solids-free) reaction mixtures are cooled to room temperature or below and treated with low-boiling tertiary amine and then acylated as was described above for the first mode of the amine-accelerated aspect of the invention.
  • Recovery and reuse of both the DSDE ⁇ H2O catalyst and low-boiling tertiary amine, isolation of the S-6-E in either solid or purified syrup form, and conversion of S-6-E to TGS-6-E may also be carried out as described above.
  • the process of the second mode follows, in general, the criteria for tertiary amine and anhydride stoichiometry, polar aprotic solvent structure, and acylation temperature set out in the discussion of the first mode.
  • the third mode of practice is diagrammed in Scheme I, shown as Fig. 1.
  • This is a continuous processing mode which involves the use of a polar aprotic acylation solvent, a hydrocarbon-like cosolvent for both the recycle extraction and dehydration of the DSDE ⁇ H2O organotin agent, a nonvolatile (i.e., substantially higher boiling than the polar aprotic solvent) tertiary amine to generate the activated complex for acylation, the isolation of solid S-6-E by crystallization (or precipitation), the recovery and recycle (in a single process stream) of both the DSDE ⁇ H2O catalyst and the nonvolatile amine, and the removal of the carboxylic acid byproduct from the process stream by extraction with a precise stoichiometric amount of aqueous sodium hydroxide.
  • the solid S-6-E produced by this process is suitable for chlorination to sucralose-6-ester.
  • Example 46 details three repetitive cycles of a process which employs DMF as the polar aprotic solvent, toluene as the extraction-dehydration cosolvent, DSDB ⁇ H2O as the organotin catalyst, N,N-dimethyloctylamine (DMOA, bp 195°C) as the nonvolatile tertiary amine, benzoic anhydride as the acylating agent, and the crystallization of S-6-B from acetone.
  • the process began by dissolving sucrose (1.00 molar equivalent) and DSDB ⁇ H2O (0.60 molar equivalent) in DMF at about 80°C.
  • This solution was dehydrated by codistillation with toluene under reduced pressure at about 90°C.
  • the mixture was then cooled to about 20°C and sequentially treated with DMOA (1.10 molar equivalents) and benzoic anhydride (1.10 molar equivalents) with continued cooling to maintain an approximately 20°C reaction temperature.
  • the DMF was removed (for direct recycle) by vacuum evaporation to produce a viscous oil (containing DSDB, S-6-B, benzoic acid, and DMOA) which was treated with acetone to give a solution from which S-6-B crystallized.
  • the carbohydrate was isolated by filtration and vacuum dried. The filtrate was vacuum evaporated to remove the acetone (for recycle) producing a viscous oil (containing DSDB, benzoic acid, and DMOA) which was contacted with toluene and water containing 1.10 molar equivalents of sodium hydroxide.
  • the benzoic acid was quantitatively extracted into the aqueous phase as its sodium salt, while the DSDB ⁇ H2O and DMOA remained in the hydrocarbon phase. (In the attached Example the aqueous sodium benzoate solution was discarded. In a commercial operation this salt would be recovered and reconverted to benzoic anhydride.)
  • the toluene was then removed (for recycle) by vacuum evaporation to produce a relatively anhydrous viscous oil composed of DSDB and DMOA, which were quantitated by, respectively, atomic absorption spectrophotometry and gas chromatography.
  • a toluene solution of the assayed oil was then treated with sucrose, DMF, and make-up DSDB ⁇ H2O and the process repeated, with make-up DMOA added at the appropriate part of the procedure.
  • Example 46 shows three consecutive cycles of this process with isolated S-6-B yields averaging 71.5% with an average purity (by HPLC analysis) of 92.7%.
  • the process of Scheme I follows, in general, the criteria for organotin agent, tertiary amine, and anhydride stoichiometry, catalyst and polar aprotic solvent structure, and acylation temperature set out in the discussion of the first mode of practice of the amine-accelerated aspect of the invention.
  • the process of Scheme I also follows, in general, the criteria regarding the use of dehydration cosolvents set out in the discussion of the second mode of practice of the amine-accelerated aspect of the invention. Note that it would be possible to practice the process of Scheme I using anhydrides other than benzoic anhydride, provided that a suitable S-6-E crystallization solvent is utilized.
  • DMOA 2,4,6-collidine (2,4,6-trimethylpyridine, bp 171°C), and N,N-dimethyldodecylamine (DMDA, bp 110°C at 3 mm of Hg)
  • DMDA N,N-dimethyldodecylamine
  • a variety of other high-boiling tertiary amines, such as tri- n -butylamine (bp 216°C), tri- n -octylamine (bp 365°C), and N-methyldi- n -octylamine (bp 162°C at 15 mm of Hg) can also be used as the nonvolatile tertiary amine component of this process.
  • the fourth mode of practice of the invention is pictured in Scheme II, shown as Fig. 2.
  • This is a continuous processing mode which involves the use of a polar aprotic acylation solvent, a hydrocarbon-like cosolvent for both the recycle extraction and dehydration of the DSDE ⁇ H2O organotin agent, a volatile (i.e., substantially lower boiling than the polar aprotic solvent) tertiary amine to generate the activated complex for acylation, the isolation of solid S-6-E by crystallization (or precipitation), the recovery and recycle of the DSDE ⁇ H2O catalyst, and the removal of the carboxylic acid byproduct from the process stream by extraction with a precise stoichiometric amount of aqueous sodium hydroxide.
  • the solid S-6-E generated by this process is suitable for chlorination to produce sucralose-6-ester.
  • Example 47 describes five repetitive cycles of a process which employees DMF as the polar aprotic solvent, toluene as the extraction-dehydration cosolvent, DSDB ⁇ H2O as the organotin agent, triethylamine as the volatile tertiary amine, benzoic anhydride as the acylating agent, and the crystallization of S-6-B from acetone.
  • the process was started by dissolving sucrose (1.00 molar equivalent) and DSDB ⁇ H2O (0.60 molar equivalent) in DMF at about 80°C. This solution was dehydrated by codistillation with toluene at about 90°C under reduced pressure. The mixture was then cooled to about 20°C and treated sequentially with TEA (1.10 molar equivalents) and benzoic anhydride (1.10 molar equivalents) with continued cooling to maintain an approximately 20°C reaction temperature.
  • the benzoic acid was quantitatively extracted into the aqueous phase as its sodium salt, while the DSDB ⁇ H2O remained in the hydrocarbon phase. (In the attached Example the aqueous sodium benzoate solution was discarded. In a commercial operation this salt would be recovered and reconverted to benzoic anhydride.)
  • Example 47 shows five consecutive cycles of this process with isolated S-6-B yields averaging 71.9% with an average purity (by HPLC analysis) of 92.4%. DSDB ⁇ H2O recovery averaged 97.1%.
  • the process of Scheme II follows, in general, the criteria for organotin catalyst, tertiary amine, and anhydride stoichiometry, organotin catalyst, tertiary amine, and polar aprotic solvent structure, and acylation temperature set out in the discussion of the first mode of practice of of the amine-accelerated aspect of the invention.
  • the process of Scheme II also follows, in general, the criteria regarding the use of dehydration cosolvents set out in the discussion of the second mode of practice of the amine-accelerated aspect of the invention. Note that it would be possible to practice the process of Scheme II using anhydrides other than benzoic anhydride, provided that a suitable S-6-E crystallization solvent is utilized.
  • the fifth mode is depicted in Scheme III, shown as Fig. 3.
  • This is a continuous processing mode which involves the use of a polar aprotic acylation solvent, a hydrocarbon-like cosolvent for both the recycle extraction and dehydration of the DSDE ⁇ H2O organotin agent, a volatile (i.e., substantially lower boiling than the polar aprotic solvent) tertiary amine to generate the activated complex for acylation, the isolation of the S-6-E as a purified syrup, the recovery and recycle of the DSDE ⁇ H2O component, and the removal of both the volatile tertiary amine and the carboxylic acid byproduct from the process stream by distillation techniques.
  • the S-6-E syrups generated by this process are suitable for conversion to sucralose-6-ester by chlorination.
  • Example 48 describes five repetitive cycles of a process which employees DMF as the polar aprotic solvent, cyclohexane as the extraction-dehydration cosolvent, DSDA ⁇ H2O as the organotin agent, triethylamine as the volatile amine, and acetic anhydride as the acylating agent.
  • the process was begun by dissolving sucrose (1.00 molar equivalent) and DSDA ⁇ H2O (1.00 molar equivalent) in DMF at about 80°C. This solution was treated with cyclohexane and dehydrated by codistillation at about 90°C. The mixture was cooled to about 20°C and treated sequentially with TEA (1.10 molar equivalents) and acetic anhydride (1.10 molar equivalents) with continued cooling to maintain an approximately 20°C reaction temperature.
  • the reaction mixture was treated with water and the DSDA ⁇ H2O recovered by extraction with cyclohexane.
  • the DMF-based solution (containing S-6-A, acetic acid, water, and TEA) was then evaporated under reduced pressure to remove the volatile amine, water, acetic acid, and a portion of the DMF (see the earlier discussion regarding the separation and recycle of these reaction components) to produce a syrup which was assayed for S-6-A and DMF content by, respectively, HPLC and gas chromatography.
  • the cyclohexane was then removed (for recycle) from the combined extracts to afford a relatively anhydrous viscous oil composed of DSDA (assayed by atomic absorption spectrophotometry).
  • Example 22 shows five consecutive cycles of this process with syrup S-6-A yields averaging 79.0%. DSDA ⁇ H2O recovery averaged 98.8%.
  • the process of Scheme III follows, in general, the criteria for organotin agent, tertiary amine, and anhydride stoichiometry, organotin agent, tertiary amine, and polar aprotic solvent structure, and acylation temperature set out in the discussion above.
  • the process of Scheme III follows, in general, the criteria regarding the use of dehydration cosolvents set out in the discussion of the second mode of practice of the amine-accelerated aspect of the invention. Additionally, the process of Scheme III follows, in general, the criteria regarding DSDE.H2O extraction and recycle set out in Vernon et al., discussed above.
  • Example 27 The experiment of Example 27 was repeated using 74.2 g (100 mmol) of DSDB ⁇ H2O as the organotin agent and 49.8 g (220 mmol) of benzoic anhydride dissolved 50 ml of DMF for acylation.
  • the benzoylation required about 60 min to reach completion (TLC analysis). Work-up afforded a syrup containing 64.7 g (145 mmol, 72.5% yield) of sucrose-6-benzoate.
  • the solids-free mixture was cooled to about 20°C, and treated in one portion with 22.3 g (220 mmol) of triethylamine.
  • the amine addition produced a mild (about 2°C) exotherm.
  • Acetic anhydride (22.5 g, 220 mmol) was then added dropwise over 10 min using ice-bath cooling as necessary to keep the reaction temperature below 25°C.
  • the reaction appeared to be complete by TLC after stirring for about 15 min at room temperature.
  • the mixture was worked-up as described in Example 27 to provide a syrup shown by HPLC analysis to contain 57.7 g (150 mmol, 75.1% yield) of sucrose-6-acetate.
  • Example 29 The experiment of Example 29 was repeated using 30.6 g (50.0 mmol) of DSDA ⁇ H2O as the organotin agent.
  • the dehydration temperature was 92°C, and the water produced was 116% of the total present (60-min reflux).
  • Acetylation and work-up afforded a syrup containing 47.6 g (124 mmol, 62.0% yield) of sucrose-6-acetate.
  • Example 29 The experiment of Example 29 was repeated using 17.4 g (220 mmol) of pyridine as the tertiary amine.
  • the dehydration temperature was 99°C, and the water produced was 66.4% of the total present (45-min reflux).
  • the acetylation required about 60 min to reach completion (TLC analysis). Work-up afforded a syrup containing 46.8 g (122 mmol, 60.9 % yield) of sucrose-6-acetate.
  • Example 29 The experiment of Example 29 was repeated using 28.4 g (220 mmol) of diisopropylethylamine as the tertiary amine.
  • the dehydration temperature was 100°C, and the water produced was 76.5% of the total present (45-min reflux).
  • Work-up afforded a syrup containing 55.7 g (145 mmol, 72.6% yield) of sucrose-6-acetate.
  • Example 29 The experiment of Example 29 was repeated using 74.2 g (100 mmol) of DSDB ⁇ H2O as the organotin agent.
  • the dehydration temperature was 102°C, and the water produced was 60.5% of the total present (30-min reflux).
  • Work-up afforded a syrup containing 58.5 g (152 mmol, 76.2% yield) of sucrose-6-acetate. No sucrose-6-benzoate could be detected in the syrup by TLC analysis.
  • Example 29 The experiment of Example 29 was repeated using 23.6 g (220 mmol) of 2,6-lutidine as the tertiary amine.
  • the dehydration temperature was 99°C, and the water produced was 78.2% of the total present (45-min reflux).
  • the acetylation required about 60 min to reach completion (TLC analysis). Work-up afforded a syrup containing 56.0 g (146 mmol, 72.9% yield) of sucrose-6-acetate.
  • Example 29 The experiment of Example 29 was repeated using 49.8 g (220 mmol) of benzoic anhydride dissolved in 50 ml of DMF for acylation.
  • the dehydration temperature was 99°C, and the water produced as 56.8% of the total present (45-min reflux).
  • the benzoylation required about 60 min to reach completion (TLC analysis). Work-up afforded a syrup containing 72.9 g (163 mmol, 81.6% yield) of sucrose-6-benzoate.
  • Example 29 The experiment of Example 29 was repeated using 148 g (200 mmol) of DSDB ⁇ H2O as the organotin agent.
  • the dehydration temperature was 99°C, and the water produced was 39.8% of the total present (30-min reflux).
  • Acetylation and work-up afforded a syrup containing 64.2 g (167 mmol, 83.5% yield) of sucrose-6-acetate.
  • Example 29 The experiment of Example 29 was repeated using 148 g (200 mmol) of DSDB ⁇ H2O as the organotin agent, 150 ml of cyclohexane as the dehydration cosolvent, and 49.8 g (220 mmol) of benzoic anhydride dissolved in 50 ml of DMF for acylation.
  • the dehydration temperature was 95°C, and the water produced was 45.6% of the total present (45-min reflux).
  • Benzoylation and work-up produced a syrup containing 77.0 g (171 mmol, 86.2% yield) of sucrose-6-benzoate.
  • Example 29 The experiment of Example 29 was repeated using 111 g (150 mmol) of DSDB ⁇ H2O as the organotin agent.
  • the dehydration temperature was 104°C, and the water produced was 46.8% of the total present (30-min reflux).
  • Acetylation and work-up afforded a syrup containing 63.8 g (166 mmol, 83.0% yield) of sucrose-6-acetate.
  • Tetraoctyldistannoxane diacetate monohydrate was prepared by dissolving 75.8 g (200 mmol) of DOTO ⁇ 1 ⁇ 2H2O in 500 ml of glacial acetic acid at room temperature (about 60 min required). Rotary evaporation (water-aspirator vacuum, 40°C bath) afforded the product as a pale-yellow viscous oil. The oil was dissolved in 500 ml of NMP, and the solution evaporated (rotary evaporator, mechanical-pump vacuum, 65°C water bath) to remove residual acetic acid. The yield was assumed to be quantitative (86.0 g, 100 mmol).
  • Example 29 The experiment of Example 29 was repeated using 148 g (200 mmol) of DSDB ⁇ H2O as the organotin agent, 150 ml of n -heptane as the dehydration cosolvent, 28.4 g (220 mmol) of diisopropylethylamine as the tertiary amine, and 49.8 g (220 mmol) of benzoic anhydride dissolved in 50 ml of DMF for acylation.
  • the dehydration temperature was 104°C, and the water produced was 40.8% of the total present (30-min reflux).
  • the benzoylation required about 60 min to reach completion (TLC analysis). Work-up afforded a syrup containing 77.9 g (175 mmol, 87.3% yield) of sucrose-6-benzoate.
  • Example 41 The experiment of Example 41 was repeated using 65.0 g (87.6 mmol) of DSDB ⁇ H2O as the organotin agent and 16.3 g (161 mmol) of triethylamine as the tertiary amine. Benzoylation and work-up afforded 54.6 g of solid shown by HPLC assay to consist of 92.0% sucrose-6-benzoate (50.2 g, 113 mmol, 77.1% yield).
  • Example 41 The experiment of Example 41 was repeated using 65.0 g (87.6 mmol) of DSDB ⁇ H2O as the organotin agent and 34.4 g (161 mmol) of N,N-dimethyldodecylamine as the tertiary amine. Benzoylation and work-up provided a syrup (containing S-6-B, DSDB, and DMDA) which, after treatment with acetone in the usual manner, afforded 46.9 g of solid shown by HPLC analysis to consist of 83.4% sucrose-6-benzoate (39.1 g, 87.6 mmol, 60.0% yield).
  • Example 41 The experiment of Example 41 was repeated using 67.2 g (90.5 mmol) of DSDB ⁇ H2O as the organotin agent and 25.3 g (161 mmol) of N,N-dimethyloctylamine as the tertiary amine. Benzoylation and work-up provided a syrup (containing S-6-B, DSDB, and DMOA) which, after treatment with acetone in the usual manner, afforded 47.3 g of solid determined by HPLC analysis to consist of 96.6% sucrose-6-benzoate (45.7 g, 102 mmol, 70.1% yield).
  • Example 41 The experiment of Example 41 was repeated using 67.2 g (90.5 mmol) of DSDB ⁇ H2O as the organotin agent and 19.5 g (161 mmol) of 2,4,6-collidine as the tertiary amine. Benzoylation and work-up provided a syrup (containing S-6-B, DSDB, and 2,4,6-collidine) which, after treatment with acetone in the usual manner, afforded 53.6 g of solid found by HPLC determination to consist of 90.6% sucrose-6-benzoate (48.6 g, 109 mmol, 74.5% yield).
  • sucrose-6-benzoate detailed in the table immediately below were conducted according to a procedure (original cycle described herein) in which sucrose (50.0 g, 146 mmol) and DSDB ⁇ H2O (65.0 g, 87.6 mmol) were dissolved in DMF (250 ml) at about 80°C.
  • the reaction mixture was treated with toluene (100 ml) and available water removed by codistillation at about 100 mm of Hg and 90°C internal temperature.
  • the solution was then cooled to room temperature and treated sequentially with 25.3 g (161 mmol) of DMOA and 36.3 g (161 mmol) of benzoic anhydride. Ice-bath cooling was employed to maintain a reaction temperature of about 20°C during the addition of anhydride.
  • the organic layer was evaporated (rotary evaporator, water-aspirator vacuum, 40°C water bath) to afford a viscous oil which was dissolved in toluene (100 ml) and analyzed for DSDB ⁇ H2O by atomic absorption spectrophotometry (63.0 g, 84.9 mmol, 96.9% recovery) and for DMOA by gas chromatography (23.0 g, 146 mmol, 90.7% recovery). The above-described process was then repeated using the toluene solution and 50 g of sucrose dissolved in 250 ml of DMF.
  • sucrose-6-benzoate delineated in the table immediately below were conducted according to a procedure (original cycle described herein) in which sucrose (50.0 g, 146 mmol) and DSDB ⁇ H2O (65.0 g, 87.6 mmol) were dissolved in DMF (250 ml) at about 80°C.
  • the reaction mixture was treated with toluene (100 ml) and available water removed by codistillation at about 100 mm of Hg and 90°C internal temperature.
  • the solution was then cooled to room temperature and treated sequentially with triethylamine (16.3 g, 161 mmol) and benzoic anhydride (36.3 g, 161 mmol). Ice-bath cooling was employed as necessary to maintain a reaction temperature of about 20°C during the addition of anhydride.
  • the organic layer was exhaustively evaporated (rotary evaporator, water-aspirator vacuum, 40°C water bath followed by mechanical-pump vacuum, 50°C water bath) to afford a viscous oil which was dissolved in toluene (100 ml) and analyzed for DSDB ⁇ H2O by atomic absorption spectrophotometry (65.0 g, 87.6 mmol, 100% recovery). The above-described process was then repeated using the toluene solution and 50 g of sucrose dissolved in 250 ml of DMF.
  • sucrose-6-acetate syrup The five sequential preparations of sucrose-6-acetate syrup detailed in the table immediately below were conducted according to a procedure (original cycle described herein) in which sucrose (68.5 g, 200 mmol) and DSDA ⁇ H2O (122 g, 200 mmol) were refluxed for 60 min in a mixture of DMF (400 ml) and cyclohexane (150 ml) with codistillative water removal (93°C dehydration temperature, 62.5% of the total water present removed). The biphasic, but solids-free, mixture was then cooled to 20°C and sequentially treated with triethylamine (22.3 g, 220 mmol) and acetic anhydride (22.5 g, 220 mmol). Ice-bath cooling was employed as necessary to maintain a reaction temperature of about 20°C during the anhydride addition.
  • the combined cyclohexane extracts were evaporated (rotary evaporator, water-aspirator vacuum, 30°C water bath) and the viscous oil thus produced dissolved in 150 ml of cyclohexane and assayed for DSDA ⁇ H2O by atomic absorption spectrophotometry (119 g, 194 mmol, 97.2% recovery).
  • the above described process was then repeated using the cyclohexane solution and 68.5 g of sucrose dissolved in 400 ml of DMF.
  • the process of Neiditch et al. is outlined as follows: The process is carried out by reacting sucrose with a di(hydrocarbyl)tin oxide such as dibutyltin oxide in an inert organic vehicle.
  • a di(hydrocarbyl)tin oxide such as dibutyltin oxide in an inert organic vehicle.
  • the hydrocarbyl groups bonded to tin can be, individually, alkyl, cycloalkyl, aryl, or arylalkyl such as, for example, methyl, ethyl, propyl, butyl, octyl, benzyl, phenethyl, phenyl, naphthyl, cyclohexyl, and substituted phenyl.
  • the preferred hydrocarbyl groups are alkyl having up to eight carbon atoms.
  • a di(hydrocarbyl)tin dialkoxide, dihalide, diacylate, or other organic tin compound can be used as long as it generates the di(hydrocarbyloxy)distannoxane in situ .
  • the DHTO and sucrose may be employed in a wide range of stoichiometric ratios. However, stoichiometric ratios of about one-to-one are preferred. This is because the use of an excess of sucrose leads to contamination of the S-6-E by sucrose and undesired sucrose esters, while the use of excess DHTO causes contamination of the S-6-E product by sucrose diesters.
  • the most preferred stoichiometric ratio uses the DHTO in a very slight (1-3%) molar excess (basis sucrose) in order to insure the near absence of sucrose in the product.
  • the process of Neiditch et al. is carried out in an inert organic reaction vehicle.
  • inert is meant that the reaction vehicle is free of any organic functional groups that will react with either the sucrose or the DHTO.
  • the inert organic reaction vehicle will be a mixed solvent system comprising a polar aprotic solvent and a cosolvent.
  • the polar aprotic solvent is employed for the purpose of dissolving the sucrose
  • the cosolvent is employed for the purpose of codistillatively removing all water generated by the reaction of sucrose with the DHTO and also promoting the solubility of the DHTO.
  • the polar aprotic solvents which can be employed include those described below with respect to the acylation step. DMF is the preferred polar aprotic solvent.
  • Cosolvents capable of codistillatively removing the water of condensation include chlorinated hydrocarbons such as chloroform, a variety of saturated and aromatic hydrocarbons such as hexane, heptane, octane, cyclohexane, benzene, and toluene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, acyclic and cyclic ethers such as tetrahydrofuran, and other inert organic liquids that meet the criteria set forth herein.
  • chlorinated hydrocarbons such as chloroform
  • saturated and aromatic hydrocarbons such as hexane, heptane, octane, cyclohexane, benzene, and toluene
  • ketones such as methyl ethyl ketone and methyl isobutyl ketone
  • acyclic and cyclic ethers such as tetrahydr
  • the primary criteria for a cosolvent are (1) that is produce a mixture with the polar aprotic solvent, the DHTO, and the sucrose, which refluxes at atmospheric pressure with an internal reaction temperature within the range of from about 75°C to about 125°C, (2) that it codistill the water produced by the condensation of the DHTO and sucrose, thereby facilitating removal of water during the reaction, and (3) that it promote the solubility of the DHTO in the reaction mixture (since DHTO's are usually not soluble to any significant degree in polar aprotic solvents) and thereby enhance the rate of reaction of the DHTO with sucrose.
  • Cosolvents which are immiscible with water and which do form a constant-composition minimum-boiling azeotrope with water are preferred, but, as has been determined by experimentation, reaction systems employing such cosolvents typically reflux at temperatures significantly higher than either the water-azeotrope boiling point or the boiling point of the pure solvent. There is also data showing that the water-cosolvent compositions of the distillates arising from these systems are not constant throughout the DHTO-sucrose condensation period.
  • Preferred cosolvents for reasons of chemical stability, efficiency of water removal, cost, and boiling point include cyclohexane, n-heptane, and isooctane.
  • the reaction between sucrose and the DHTO is carried out at a temperature within the range of from about 75°C to about 125°C. Below 75°C, the reaction becomes uneconomically slow, and above 125°C there is a tendency for the carbohydrate to decompose.
  • the preferred reaction temperature is within the range of about 80°C to about 100°C, and more preferably, from about 85°C to about 90°C.
  • the product of the reaction of sucrose and DHTO is a 1,3-di-(6-O-sucrose)-1,1,3,3-tetra(hydrocarbyl)distannoxane, which may be acylated as described below.
  • acylating agent Basis sucrose
  • the selection of the particular acylating agent to be used in the acylation reaction is dictated in part by the use to which the acylated product is to be put. For example, if the acyl group is being employed as a blocking group, as it would be in the preparation of the artificial sweetener as discussed above in the Background of the Invention section of this application, an acylating agent such as benzoic or acetic anhydride would be employed because it is inexpensive, the acyl group is readily removed at an appropriate stage of the synthesis, and it is stable to reactions that the acylated compound must undergo prior to removal of the acyl group. If a S-6-E is to be the ultimate product of the synthesis, then the acylating agent used is the one that will generate the desired acyl group for the ester product.
  • acylating agents that can be used are the various anhydrides of benzoic and substituted benzoic acid (e.g., 4-nitrobenzoic acid, 3,5-dinitrobenzoic acid, and the like), alkanoic acids such as acetic acid, propionic acid, butyric acid, cyclohexanecarboxylic acid, long chain fatty acids, both saturated and unsaturated, such as stearic acid, oleic acid, linoleic acid, and the like, having up to, for example, 28 carbon atoms, unsaturated acids such as acrylic acid and methacrylic acid, substituted acids such chloroacetic acid, cyanoacetic acid, phenoxyacetic acid, and the like, and saturated and unsaturated dicarboxylic acids such as phthalic acid, maleic acid, glutaric acid, and the like.
  • alkanoic acids such as acetic acid, propionic acid, butyric acid, cyclohexanecarboxylic acid, long chain
  • the acylation reaction is carried out in an inert organic reaction vehicle such as DMF or other polar aprotic solvents such as DMSO, NMP, DMA, HMPA, and other polar aprotic solvents in which sucrose is soluble.
  • DMF is the preferred polar aprotic solvent because of its low cost, its relatively low boiling point, and its suitability as a solvent for further steps in the process for producing sucralose.
  • the acylation reaction is carried out at a temperature and for a period of time sufficient to prepare the S-6-E product.
  • the anhydride is a liquid, it may be added neat to the sucrose-organotin adduct, or it may be diluted with an inert cosolvent. If the anhydride is a solid, it may be added in the solid for or added as a solution in an appropriate inert solvent. The anhydride may be added all at once, or it may be added slowly over a period of time.
  • Anhydride stoichiometry is an important aspect of the successful practice of this invention.
  • the use of too little anhydride will result in a S-6-E product contaminated by residual sucrose.
  • the use of too much anhydride will cause sucrose diester contamination.
  • the most preferred stoichiometric ratio uses the anhydride in a slight (5-10%) molar excess (basis sucrose) in order to insure the near absence of sucrose in the product.
  • Acylation temperatures from below 0°C to about 30°C have been employed experimentally.
  • the upper limit of acceptable acylation temperatures is governed by the onset of thermally activated nonregioselective acylation reactions which will result in the formation of undesirable sucrose mono- and diesters. From a practical standpoint, this temperature limit is a function of the reactivity of the acid anhydride. For example, because acetic anhydride is a relatively reactive species, acylations with it are normally carried out below about 20°C. Benzoic anhydride, on the other hand, being somewhat less reactive, allows for acylation at room temperature or slightly above.
  • acylation reactions are mildly exothermic. Depending upon initial reaction temperature and rate of anhydride addition to the di(hydrocarbyl)tin-sucrose adduct, external cooling of the acylation process might be required in order that thermally activated nonregioselective acylation be minimized.
  • the times required for the acylations of the sucrose adducts to go to completion are dependent upon the concentration of the reactants (as the acylation is a multiple-order process), the reactivity of the acylating agent, and the temperature of the reaction mixture. Although times of from one hour to several days have been employed in the laboratory, there is no advantage to extending the reaction period longer than that time necessary for consumption of the acylating agent. This is generally complete within from about one to about five hours under typical conditions.
  • the products of the acylation reaction are a sucrose-6-ester and a distannoxane diester.

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US5298611A (en) * 1993-03-12 1994-03-29 Mcneil-Ppc, Inc. Sucralose pentaester production
DK0776903T3 (da) 1995-11-28 2003-05-12 Mcneil Ppc Inc Fremgangsmåde til fremstilling af en saccharose-6-ester
GB2365424B (en) * 2000-07-31 2002-06-26 Tate & Lyle Plc An improved method for the synthesis of sucrose-6-esters
US20090105470A1 (en) * 2005-02-22 2009-04-23 Pharmed Medicare Private Limited , A Corporation Tin Mediated Regioselective Synthesis of Sucrose-6-Esters
CN100418976C (zh) 2006-04-03 2008-09-17 广州科宏食品添加物有限公司 一种三氯蔗糖的制备方法
GB0702854D0 (en) * 2007-01-09 2007-03-28 Tate & Lyle Plc Method for the synthesis of sucrose-6-esters
GB2469158B (en) * 2009-03-31 2011-09-28 Peter J Seaberg Base-assisted formation of tin-sucrose adducts
GB2474310B (en) * 2009-10-12 2012-02-29 Tate & Lyle Technology Ltd Process for the production of sucrose-6-ester
GB2474311B (en) 2009-10-12 2012-10-17 Tate & Lyle Technology Ltd Low temperature, single solvent process for the production of sucrose-6-ester
GB201110520D0 (en) * 2011-05-10 2011-08-03 Tate & Lyle Technology Ltd Extraction of carboxylic acids with tin compounds
JP5679447B2 (ja) * 2011-06-20 2015-03-04 第一工業製薬株式会社 ショ糖ベンゾエート組成物の製造方法
CN107459540A (zh) * 2017-08-28 2017-12-12 山东三和维信生物科技有限公司 用于三氯蔗糖生产的节省dmf及提高蔗糖‑6‑酯产率的方法
CN111592574A (zh) * 2020-05-22 2020-08-28 安徽金禾实业股份有限公司 一种蔗糖-6-乙酸酯工业精制方法
CN112495442A (zh) * 2020-12-02 2021-03-16 安徽金禾实业股份有限公司 一种蔗糖-6-乙酯生产中回收制备有机锡催化剂的方法

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